Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats

Abstract

Metabolic syndrome is associated with an increased risk of colorectal cancer. This study investigated the impact of hypertension, a component of metabolic syndrome, on azoxymethane (AOM)-induced colorectal carcinogenesis using SHRSP/Izm (SHRSP) non-diabetic/hypertensive rats and SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic/hypertensive rats. Male 6-week-old SHRSP, SHRSP-ZF, and control non-diabetic/normotensive Wister Kyoto/Izm (WKY) rats were given 2 weekly intraperitoneal injections of AOM (20 mg/kg body weight). Two weeks after the last injection of AOM, the SHRSP and SHRSP-ZF rats became hypertensive compared to the control WKY rats. Serum levels of angiotensin-II, the active product of the renin-angiotensin system, were elevated in both SHRSP and SHRSP-ZF rats, but only the SHRSP-ZF rats developed insulin resistance, dyslipidemia, and hyperleptinemia and exhibited an increase in adipose tissue. The development of AOM-induced colonic preneoplastic lesions and aberrant crypts foci, was significantly accelerated in both SHRSP and SHRSP-ZF hypertensive rats, compared to WKY normotensive rats. Furthermore, induction of oxidative stress and exacerbation of inflammation were observed in the colonic mucosa and systemically in SHRSP and SHRSP-ZF rats. Our findings suggest that hypertension plays a role in the early stage of colorectal carcinogenesis by inducing oxidative stress and chronic inflammation, which might be associated with activation of the renin-angiotensin system.

Figure 1

ACF developed in the SHRSP, SHRSP-ZF, and WKY rats that received AOM. (A) Representative morphology of ACF (arrows) induced by AOM stained with methylene blue in Group 2. Magnification, 40×; (B) Average number of ACF and ACs (/cm²). Group 1: WKY rats, Group 2: SHRSP rats, and Group 3: SHRSP-ZF rats. The values are expressed as mean ± SD. * p < 0.05.

Figure 2

Measures of oxidative stress and antioxidant biomarkers’ expression. (A) Urine 8-OHdG levels were measured by enzyme immunoassay; (B) Hydroperoxide levels in the serum were determined by the d-ROM test; (C) The expression levels of GPx and CAT mRNA in the colonic epithelium were examined by quantitative real-time RT-PCR using specific primers. The values are expressed as mean ± SD. * p < 0.01, ** p < 0.01.

Figure 3

Serum levels of TNF-α, IL-6, and COX-2 and the expression levels of TNF-α, MCP-1, and iNOS mRNA in the colonic epithelium. (A) The serum concentrations of TNF-α, IL-6, and COX-2 were measured by enzyme immunoassay; (B) The expression levels of TNF-α, MCP-1, and iNOS mRNA in the colonic epithelium were examined by quantitative real-time RT-PCR using specific primers. The values are expressed as mean ± SD. * p < 0.01, ** p < 0.05.